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Structural and mechanistic insights into the association of PKCα-C2 domain to PtdIns(4,5)P2

AuthorsGuerrero-Valero, Marta; Ferrer-Orta, Cristina ; Querol-Audí, Jordi ; Marín-Vicente, Consuelo; Fita, Ignacio ; Gómez-Fernández, Juan C.; Verdaguer, Núria ; Corbalán-García, Senena
KeywordsCalcium phosphoinositides
Peripheral membrane proteins
Issue Date21-Apr-2009
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences of the United States of America 106(16): 6603-6607 (2009)
AbstractC2 domains are widely-spread protein signaling motifs that in classical PKCs act as Ca2+-binding modules. However, the molecular mechanisms of their targeting process at the plasma membrane remain poorly understood. Here, the crystal structure of PKCα-C2 domain in complex with Ca 2+, 1,2-dihexanoyl-sn-glycero-3-[phospho-L-serine] (PtdSer), and 1,2-diayl-sn-glycero-3-[phosphoinositol-4,5-bisphos-phate] [Ptdlns(4,5)P2] shows that PtdSer binds specifically to the calcium-binding region, whereas Ptdlns(4,5)P2 occupies the concave surface of strands β3 and β4. Strikingly, the structure reveals a Ptdlns(4,5)P2-C2 domain-binding mode in which the aromatic residues Tyr-195 and Trp-245 establish direct interactions with the phosphate moieties of the inositol ring. Mutations that abrogate Tyr-195 and Trp-245 recognition of Ptdlns(4,5)P2 severely impaired the ability of PKCα to localize to the plasma membrane. Notably, these residues are highly conserved among C2 domains of topology I, and a general mechanism of C2 domain-membrane docking mediated by Ptdlns(4,5)P 2 is presented.
Publisher version (URL)http://dx.doi.org/10.1073/pnas.0813099106
Identifiersdoi: 10.1073/pnas.0813099106
issn: 0027-8424
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